The compounds of formula I and related formulae preferably are inhibitors of dihydroorotate dehydrogenase (DHODH or DHOD). DHODH is a protein which catalyzes the fourth step in de novo pyrimidine nucleotide pathway. (Greene et al. Biochem Pharmacol 1995, 50:861-7; Davis J. P et al. FASEB J 1996, 10(6): Abst C23). It catalyses the only oxidation/reduction reaction in that pathway which is the step of converting DHO (dihydroorotate) to orotate with the aid of flavin cofactor and an electron acceptor.
Inhibitors of dihydroorotate dehydrogenase have found wider application as chemotherapeutic agents. Initially explored as anticancer drugs (Kensler et al. 1989 in: Design of Enzyme Inhibitors as Drugs; Sandler, M., and Smith, H. J. Eds., pp 379-401 Oxford Univ Press, Oxford England; Cody et al. Am. J. Clin. Oncol. 16, 526-528 (1993)). As an example for DHODH inhibitors, the quinoline derivative Brequinar (6-Fluoro-2-(2′-fluoro[1,1′-biphenyl]-4-yl)-3-methyl-4-quinolinecarboxylic Acid) exhibits an anticancer activity towards L1210 murine leukemia. (Andreson L W. Et al. Cancer Commun. 1989; 1(6):381-7; Chen S F. et al. Cancer Res. 1986 October; 46(10):5014-9.). It has also been shown that Brequinar potentiates 5-fluorouracil antitumor activity in a murine model colon 38 tumor by tissue-specific modulation of uridine nucleotide pools. (G Pizzorno et al. Cancer Res. 1992 Apr. 1; 52:1660-5.)
DHODH inhibitors have also been suggested as antibiotics, especially against Helicobacter Pylori (Marcinkeviciene et al. Biochem Pharmacol. 2000, 60, 339; Haque, T. S. et al., J. Med. Chem. 2002, 45, 4669-4678), useful for treating Plasmodium falciparum related diseases (Heikkila, T. et al. J Med. Chem. 50: 186-91 (2007); Heikkila, T. et al. Bioorg Med Chem. Lett. 16: 88-92 (2006)), and as antifungal agents (Gustafson, G. et al. Curr. Genet. 1996, 30, 159).
DHODH inhibitors can also be useful for the treatment of viral mediated diseases (see U.S. Pat. No. 6,841,561).
Furthermore, inhibition of DHODH is a promising target for treating transplant rejection, rheumatoid arthritis, psoriasis as well as autoimmune diseases (Kovarik, J. M. et al. Expert Opin. Emerg. Drugs 2003, 8, 47.; Allison, A. C. Transplantation Proc. (1993) 25(3) Suppl. 2, 8-18); Makowka, L., Immunolog Rev. (1993) 136, 51-70; Davis J. P et al. Biochemistry 1996, 35:1270-3.).
Leflunomide, a well known DHODH inhibitor is a synthetic, low-molecular weight drug of the isoxazole class (see EP0527736, JP 1993506425, JP 1999322700, JP 1999343285, U.S. Pat. No. 5,494,911, U.S. Pat. No. 5,532,259, WO19991017748). This drug is currently marketed and used in the treatment of Rheumatoid arthritis and is also under evaluation for use in the treatment of inflammatory bowel disease and chronic allograft rejection.
In vivo, Leflunomide is quickly transformed in its active metabolite Teriflunomide that exerts its anti-inflammatory, antiproliferative and immunosuppressive effects via mechanisms that are not completely understood. Teriflunomide is not only a potential inhibitor of protein tyrosine kinase in vivo but a 100-1,000-fold greater inhibitor of DHODH (Davis J. P et al. FASEB J 1996, 10(6):Abst C23; Davis J. P et al. Biochemistry 1996, 35:1270-3.).
Another study examined the activity of Teriflunomide on the proliferation of spleen colony-forming units (CFU) and shows that Teriflunomide in a dose-dependently manner inhibited CFU cycling (Milenkovic, P. et al. Exp Hematol 1995, 23: Abst 121.). The effects of Teriflunomide on the behavioral consequences of experimental allergic encephalomyelitis (EAE) were assessed in female Lewis rats to determine the drug's potential utility in multiple sclerosis. Oral treatment with Teriflunomide at 3 and 10 mg/kg or with dexamethasone at 1 mg/kg began 10 days after inoculation with guinea pig spinal cord and Freund's adjuvant, when clonal expansion of inflammatory and immune cells had already occurred. Both compounds caused a significant delay in the onset of disease and in symptom severity (Styren, S. D. et al. Beneficial effects of Teriflunomide in experimental allergic encephalomyelitis. 34th Annu Meet Soc Neurosci (October 23-27, San Diego) 2004, Abst 344.5.).
Teriflunomide was tested in a phase II study in 179 patients with multiple sclerosis with relapses. Once-daily oral treatment with this drug (7 and 14 mg) for 369 weeks led to a reduced number of unique active lesions as compared to placebo. (Li, D. K. B. et al. Multiple Scler 2004, 10(Suppl. 2): Abst P685.)
An increasing number of patients affected by autoimmune and related diseases require new drugs that can treat such diseases. There is still a crucial need for immunosuppressive agents that are further useful in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis, multiple sclerosis, type I diabetes mellitus, inflammatory bowel diseases, biliary cirrhosis, uveitis and other disorders such as Crohn's diseases, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma. They are also useful as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias, alone or in combination with classic antitumoral compounds well known by the one skilled in the art.